Chi-Fong Lin

A direct anionic cyclization of 2-alkynylbenzonitrile to 3-substituted-1(2H)-isoquinolones and 3-benzylideneisoindol-2-ones initiated by methoxide addition

Treatment of 2-(2-alkylethynyl)benzonitrile with sodium methoxide in refluxing methanol for 12 h gave 3-alkyl-1(2H)-isoquinolone in modest yield. Under the same reaction conditions, methanolysis of 2-(2-arylethynyl)benzonitrile lead to the formation of 3-alkylidene isoindol-1-one. Partial hydrolysis of 2-(1-hexynyl)benzonitrile to the corresponding benzamide, followed by treatment of the benzamide with sodium methoxide in refluxing methanol gave 3-pentylidene isoindol-1-one in 49% yield. This suggests that the benzamide is not involved in this cyclization reaction.

Biradical formation from molecules with (Z)-7-sulfonyl-3-hexen-1,5-diyne functionalities

Abstract Molecule that contains (Z)-7-sulfonyl-3-hexen-1,5-diyne functionalities undergoes base-catalyzed isomerization to (Z)-eneyne-allene-sulfone and subsequent Myers cyclization to form aromatic products, presumably via a biradical intermediate. In the presence of a nucleophile, (Z)-eneyne-allene-sulfone served as a good Michael acceptor.

Substituent effect on anionic cycloaromatization of 2-(2-substituted ethynyl)benzonitriles and related molecules

Methanolysis of 2-(2-substituted ethynyl)benzonitriles based on the nature of substituents gave 5-exo product, isoindolones and 6-endo product, isoquinolones, respectively. When a bulky substituent, such as tert-butyl group, was employed in this cyclization reaction, a 5-exo adduct was obtained. Phenyl and thienyl groups which can stabilize the α-anion affect the cyclization reaction to produce the 5-exo adducts. Pyridinyl and pyrazinyl groups can also stabilize the α-anion, but the formation of a more stable intermediate by coordination of sodium with nitrogen atom leads to the 6-endo products.

Palladium-catalyzed coupling of aryl iodides with 2-alkynylbenzonitriles

Abstract The reaction of 2-(2-phenylethynyl)benzonitrile ( 1a ) with aryl iodides, in the presence of Pd(PPh 3 ) 4 and NaOCH 3 in CH 3 OH, at refluxing temperature for 24 h, gave 3-diarylmethylideneisoindoles 3a – d in 18–56% yields. When 2-(1-hexynyl)benzonitrile ( 1b ) was employed in this reaction, isoquinolines 2a – c were obtained in 29–34% yields and isoindoles 3e – g were obtained in 12–25% yields, respectively. Reaction of 2-ethynylbenzonitrile ( 1c ) with 2.5 equiv. of iodobenzene for 48 h gave 3a in 45% yield along with the monocoupled adduct 3h in 6% yield.

Molecular design, chemical synthesis and biological studies of novel enediynes related to dynemicin a

Abstract Two novel enediynes 1 and 2 and related molecules containing a (Z)-7-sulfonyl-3-hepten-1,5-diyne functionality and quinoline moiety related to dynemicin A were synthesized from quinoline and 4-methoxyquinoline, respectively. The key synthetic features involve (1) magnesium acetylide addition to the 1-acylsalt of the quinolines (2) a Pd(0)Cu(I) catalyzed coupling reaction of vinyl chloride or aryl iodide with acetylenes (3) conversion of the alcohol to a sulfide, followed by oxidation to a sulfone. These molecules proved to be active against the growth of leukemia, colon, epidermoid and melanoma cancer cell lines.

2-(6-Aryl-3(Z)-hexen-1,5-diynyl)anilines as a New Class of Potent Antitubulin Agents

Compounds 2a- h and 6 displayed significant GI 50 values of 10(-7)-10(-6) M against various cancer cell lines. Of these compounds, 2-(6-(2-trifluoromethylphenyl))-3(Z)-hexen-1,5-diynyl)aniline (2c) showed the most potent growth inhibition activity. Compound 2c also arrested cancer cells in the G2/M phase and in low concentration reduced a significant percentage of MDA-MB-231/ATCC breast cancer tetraploid cells. In addition to the G2/M block, compound 2c caused microtubule depolymerization and induced apoptosis via activation of the caspase family.

Cytotoxicities and Topoisomerase I Inhibitory Activities of 2‐[2‐(2‐Alkynylphenyl)ethynyl]benzonitriles, 1‐Aryldec‐3‐ene‐1,5‐diynes, and Related Bis(enediynyl)arene Compounds

The activities of a series of acyclic enediynes, 2-(6-substituted hex-3-ene-1,5-diynyl)benzonitriles (1–5) and their derivatives 7–23 were evaluated against several solid tumor cell lines and topoisomerase I. Compounds 1–5 show selective cytotoxicity with Hepa cells, and 2-[6-phenylhex-3-ene-1,5-diynyl]benzonitrile (5) reveals the most-potent activity. Analogues 8–10 and 13–22 also have the same effect with DLD cells; 1-[(Z)-dec-3-ene-1,5-diynyl)-4-nitrobenzene 21 shows the highest activity among them. Moreover, 1-[(Z)-dec-3-ene-1,5-diynyl]-2-(trifluoromethyl)benzene (20) exhibits the strongest inhibitory activity with the Hela cell line. Derivatives 9, 10, 18, and 23 display inhibitory activities with topoisomerase I at 87 μM. The cell-cycle analysis of compound 5, which induces a significant blockage in S phase, indicates that these novel enediynes probably undergo other biological pathways leading to the cytotoxicity, except the inhibitory activity toward topoisomerase I.

Synthesis and biological evaluation of novel symmetry bis-enediynes.

A series of acyclic symmetry bis-enediynes have been synthesized successfully and their bioactivities were evaluated. Among them, 1,6-bis(4-((2-(pyridin-2-ylethynyl)phenyl)ethynyl)phenoxy)hexane 8g showed good inhibition activity against the CCRF-CEM (GI(50)=0.04 microM) and HL-60 (GI(50)=0.09 microM) cell lines of human leukemia. The cell cycle analysis shows that compound 8g arrests cell cycle via inhibiting Cyclin A and Cyclin B expressions in low concentration and induces a significant apoptosis progress in high concentration.

Thermolysis of 2-(3-phenylsulfonylprop-1-ynyl)benzonitrile: an aza-Myers type cyclization to isoquinolines

Thermolysis of 2-(3-phenylsulfonylprop-1-ynyl)benzonitrile (3) in refluxing benzene containing cyclohexa-1,4-diene and triethylamine gave isoquinolone 4 in 7% yield and compound 5 in 10% yield and 14% of the starting material was recovered. When this cyclization reaction was carried out under oxygen atmosphere, compound 4 was isolated in 14% yield and 20% of the starting benzonitrile 3 was recovered. Under refluxing carbon tetrachloride, cyclization of 3 gave the chloroisoquinoline 6 in 18% yield and 5 in 22% yield. The isolation of compounds 4 and 6 strongly suggests the formation of biradical 8 through a (Z)-hexa-2,4,5-trienenitrile intermediate 7.